1. Field of the Invention
The invention relates generally to methods of manipulating manganese levels to alter reverse transcriptase activity, and more specifically to methods of identifying agents that modulate reverse transcriptase activity, to agents identified using such methods, and to methods of using such agents to modulate reverse transcriptase activity, for example, in a cell.
2. Background Information
Viral infection and replication in host cells is associated with various diseases in plants and animals. Retroviruses, for example, are a type of virus that associated with various cancer and with human immunodeficiency virus (HIV), which is responsible for AIDS in humans. As such, the morbidity and mortality associated with viral infections and the disease associated with such infections causes great suffering and further results in a great economic burden on individuals and society.
HIV was identified as the causative agent of AIDS in 1983 and, AIDS has progressed to being one of the greatest health problems in the world, with medical and social consequences likely to extend long into the future. The World Health Organization has estimated that between eight and ten million people are currently infected with HIV, and that approximately ten times as many individuals will be affected in the next decade. Further, the large pool of HIV carriers and the failure of HIV infection to cause early and easily identified symptoms makes the development of effective antiviral treatments a medical priority.
Retroviruses such as HIV replicate through an RNA intermediate as part of their life cycle. All retroviruses encode proteins that are required for their replication and transmission, including, for example, an integrase that allows the virus to integrate into the genomic DNA of an infected cell, and a reverse transcriptase that is involved in replication of the retrovirus genome. The activities of these retroviral proteins, including the reverse transcriptase, are central to the replication of retroviruses and, therefore, have been the target of drugs to treat retroviral infection, including HIV infection. Reverse transcriptase inhibitors are the current treatment of choice for AIDS patients. However, retroviral therapy, as for other viral therapies, are commonly of limited effectiveness due to development of viral resistance to the drug.
In an effort to overcome problems associated with the development of resistance to a single drug, “cocktails” containing a combination of drugs have been used, and have been shown to be effective for longer periods of time. Unfortunately, drugs that are effective in inhibiting the activity of retroviral proteins often inhibit normal proteins involved in survival and proliferation of the retroviral infected cells, thus causing undesirable and often severe side effects. Thus, a need exists for developing agents and methods for more effectively and specifically inhibiting retroviral enzymes without substantially affecting normal cellular enzymes. The present invention satisfies this need provides additional advantages.